(4-(3-(polyazaheterocyclic)alkanoyl)phenoxy)alkanoic acids

ABSTRACT

(4-(3-(POLYAZAHETEROCYCLIC) ALKANOYL)PHENOXYL)ALKANOIC ACIDS, A CLASS OF COMPOUNDS POSSESSING DIURETIC AND SALURETIC PROPERTIES FOR USE IN TREATING CONDITIONS ASSOCIATED WITH ELECTROLYTE AND FLUID RETENTION AND PREPARED BY THE ADDITION OF A POLYAZAHETEROCYCLE TO A (4-(2-ALKYLIDENACYL)PHENOXY) ALKANOIC ACID IN THE PRESENCE OF A BASE FOLLOWD BY ACIDIFICATION TO PRECIPITATE THE PRODUCT.

United States Patent 3,585,199 {4-[3-(POLYAZAHETEROCYCLIC)ALKANOYL]PHENOXY}ALKANOIC ACIDS Edward J. Cragoe, In, Lansdale, Pa., assignor t0Merck & Co., Inc., Rahway, NJ.

N0 Drawing. Filed May 25, 1967, Ser. No. 641,122 Int. Cl. C07d 57/48U.S. Cl. 260-456 3 Claims ABSTRACT OF THE DISCLOSURE This inventionrelates to {4-[3-(polyazaheterocyclic) alkanoyl]phenoxy}alkanoic acids(I) and a method of preparing the same, of the following generalformula:

wherein R is a straight or branched chain lower alkyl radical such asmethyl, ethyl, propyl, isopropyl and the like or trifluoromethylsubstituted lower alkyl such as 2,2,2-trifluoroethyl,2,2,2-trifluoroisopropyl, etc.; R is hydrogen or a straight or branchedchain lower alkyl radical; R is a polyazaheterocyclic radical selectedfrom the group consisting of l-pyrazolyl, l-imidazolyl, 1,2,4-triazol- 1-(or 4) -yl, 1,2,3-triazol-1 (or. 2) -yl, 1 (or 2) -tetraazolyl,l-benzimidazolyl, 1 (or 2) -indazolyl, l(lH) [or3(3H)]-imidazo[4,5-b]-pyridyl and the homologous lower alkyl derivativesof the aforesaid radicals as, for example, the methyl, ethyl, propyl,isopropyl, etc. derivatives and l,2,3,6 tetrahydro 1,3 di lower alkyl-2,6 dioxopurin-7 (or 9) -yl; X is hydrogen, a straight or branched chainlower alkyl radical, halogen such as chlorine, bromine, iodine orfluorine, or, when taken together, two X radicals on adjacent carbonatoms of the benzene ring may be joined to form a 1,3-butadienylenelinkage, i.e. CH=CHCH=CH; m is an integer from 1 to 4 and n is aninteger from 1 to 4.

The products of this invention are diuretic and saluretic agents whichcan be used in the treatment of conditions associated with electrolyteand fluid retention and hypertension. When administered in therapeuticdosages, in conventional vehicles, the instant products effectivelyreduce the amount of sodium and chloride ions in the body, lowerdangerous excesses of fluid levels to acceptable limits and, in general,alleviate conditions usually associated with edema.

A preferred embodiment of the invention, i.e., compounds which possessthe greatest diuretic and saluretic activity, are the {4- [3(polyazaheterocyclic)alkanoyl] phenoxy}acetic acids (Ia) which have thefollowing general formula:

"ice

wherein R is a straight or branched chain lower alkyl radical such asmethyl, ethyl, propyl, isopropyl and the like or trifluoromethylsubstituted lower alkyl such as 2,2,2-trifiuoroethyl,2,2,Z-trifluoroisopropyl, etc.; R is a polyazaheterocyclic radicalselected from l-pyrazolyl, 1 (or 3) -1H (or 3H)-imidazo[4,5-b]-pyridil,l-imidazolyl, 1,2,4-triazol-l (or 4) -yl and the homologous lower alkylderivatives of the aforesaid radicals and 1,2,33,6-tetrahydro-l,3-di-lower alkyl-2,6-dioxopurin-7 (or 9) -yl; and X and Xare hydrogen, a straight or branched chain lower alkyl radical, halogenor taken together with the carbon atoms of the benzene ring to whichthey are attached they may be joined to form a 1,3-butadienylenelinkage.

The instant compounds are prepared by the. addition of apolyazaheterocycle to a [4-(Z-alkylidenacyl)phenoxy] alkanoic acid,preferably in the presence of a base, followed by acidification, viz:

wherein R, R R X, m and n are the same as described hereinbefore and His the cation derived from an organic or inorganic acid such ashydrochloric acid, sulfuric acid, nitric acid and the like. If the baseis employed it forms a salt with the. acid and also catalyzes theaddition of the polyazaheterocycle to the double bond as shown above.The salt of the product formed is usually water soluble but, uponacidification, precipitates out as the acid product which can bepurified by recrystallization from a suitable solvent. Such bases assodium bicarbonate, sodium carbonate, sodium hydroxide and the like maybe used. Recrystallization can be carried out preferably using polarsolvents such as lower alkanols (e.g. ethanol and isopropyl alcohol) anddimethylformamide or from mixtures of the foregoing with non-polarsolvents (e.g. ether). Optimally, a large excess of thepolyazaheterocycle is used, the reaction time is fairly long and it iscarried out at lower temperatures, preferably at or below roomtemperature, and at a pH of about 7-10, preferably towards the higherpH. Dimethylformamide may be used to increase the solubility of thestarting acid and/ or the salt formed therefrom upon addition of thebase.

Illustrative, but non-limitative, examples of the preparation of theinstant compounds are as follows:

EXAMPLE 1 {2,3 dichloro 4 [l-oxo 2 ethyl 3(1,2,3,6-tetrahydro-1,3-dimethyl 2,6 dioxopurin-7 (or 9) -yl)propyl]phenoxy}acetic acid A solution of [2,3-dichloro-4-(2methylenebutyryl)- phenoxy1acetic acid (6.06 g., 0.02 mole) in water m1)is treated with sufficient 5% aqueous sodium hydroxide to maintain a pHof 7.1. Theophylline (3.6 g., 0.02 mole) is added and the solution isstirred at C. for 16 hours. The solution is filtered and acidified withconcentrated hydrochloric acid (2 ml.) to yield 5.4 g. (56%) of {2,3dichloro 4 [1 oxo 2 ethyl 3 (1,2,3,6- tetrahydro 1,3 dimethyl 2,6dioxopurin-7 (or 9) -yl)propyl]phenoxy}acetic acid which afterrecrystallization from ethanol (60 ml.) melts at 205207 C.

Analysis for C H Cl N,O .Calculated (percent): C, 49.70; H, 4.17; N,11.59; Cl, 14.67. Found (percent): C, 49.80; H, 4.31; N, 11.38; Cl,14.44.

EXAMPLE 2 {2,3-dichloro-4- [2-ethyl-3-( l-imidazolyl)propionyl]phenoxy}acetic acid hydrochloride A solutio of 2,3-dichloro 4(2-methylenebutyryl)- phenoxy]acetic acid (9.1 g., 0.03 mole) and sodiumbicarbonate (2.52 g., 0.03 mole) in water (150 ml.) is

treated with imidazole (2.04 g., 0.03 mole) and stirred at roomtemperature for 16 hours. The water is removed by distillation atreduced pressure at 50 C. and the residue is dissolved in ethanol (50ml.). Ether (100 ml.) and concentrated aqueous hydrochloric acid (4 ml.)are added causing the precipitation of sodium chloride which is removedby filtration. The filtrate is dried over anhydrous sodium sulfate,filtered and heated with additional ether (500 ml.) with precipitates5.9 g. (41%) of {2,3-dichloro- 4-[2 ethyl 3(1-imidazolyl)propionyl]phenoxy}acetic acid hydrochloride, which afterrecrystallization from a mixture of isopropyl alcohol and ether melts at169- 173 C.

Analysis for C H Cl O .Calculated (percent): C, 47.14; H, 4.20; N, 6.87.Found (percent): C, 46.97; H, 4.08; N, 6.86.

EXAMPLE 3 {2,3-dichloro-4- 2-( 1-pyrazolylmethylbutyryl1 phenoxy}aceticacid To a solution of sodium bicarbonate (2.52 g., 0.03 mole) in water(150 ml.) is added [2,3-dichloro-4-(2- methylenebutyryl)phenoxy]aceticacid (9.09 g., 0.03 mole). Then pyrazole (2.04 g., 0.03 mole) is addedand the resulting solution is allowed to stand at room temperature.After 66 hours, the clear reaction solution is made acid to Congo redpaper by the addition of 6 N hydrochloric acid. The resultingprecipitate that separates is recrystallized from ethanol to give Whiteneedles; the yield is 8.92 g. (80%). M.P. 170171. Further purificationby recrystallization from acetonitrile gives {2,3-dichloro 4[2-(1-pyrazolylrnethylbutyryl]phenoxy}acetic acid melting at 174-175.

Analysis for C H Cl N O .Calculated (percent): C, 51.77; H, 4.34; N,7.55. Found (percent): C, 51.92; H, 4.31; N, 7.76.

EXAMPLE 4 {2,3-dichloro-4- [2-( l-benzimidazolymethyl) bu tyryl]phenoxy}acetic acid To a solution of sodium bicarbonate (2.52 g., 0.03mole) in water (150 ml.), is added [2,3-dichloro-4-(2-methylenebutyryl)phenoxy]acetic acid (9.09 g., 0.03 mole). Thenbenzimidazole (3.54 g., 0.03 mole) is added and the resulting solutionis stirred at room temperature. After 45 hours, the reaction solution isfiltered and the clear filtrate is made acid to Congo red paper by theaddition of 6 N hydrochloric acid. The white solid that separates iscollected by filtration, washed with water and dried; the yield is 11.68g. Recrystallization from ethanol gives 9.82 g. (78%) of{2,3-dichloro-4-[2-(1-benzimidazolylmethyl)butyryl]phenoxy}acetic acidin the form of white prisms, M.P. 186-187.

Analysis for C H Cl N O .Calculated (percent): C, 57.02; H, 4.31; N,6.65. Found (percent): C, 57.01; H, 4.15; N, 6.81.

4 EXAMPLE 5 {2,3-dichloro-4-[2-(1- (or 2) -indazolymethyl)butyryl]phenoxy}acetic acid To a solution of sodium bicarbonate (2.52 g., 0.03mole) in water ml.) is added [2,3 dichloro 4 (2-methylenebutyryl)phenoxy]acetic acid (9.09 g., 0.03). Then a suspensionof indazole (3.54 g., 0.3 mole) in water (50 ml.) is added. Solution iselfected by the addition of water (450 ml.), adjusting the pH to 8.0with aqueous sodium hydroxide solution and warming on a steam bath for 5minutes. The resulting solution is allowed to stand at room temperature.After 48 hours, the clear reaction solution is acidified to a pH of 4.0by the addition of 6 N hydrochloric acid. The solid that separates isisolated by filtration, washed with water and dried; the yield is 12.00g. After grinding under ether, filtering and washing with ether, thereis obtained 7.66 g. of a white solid, M.P. 148- 151. Furtherpurification by recrystallization from isopropyl alcohol gives 6.34 g.(50%) of {2,3-dichloro4-[2- 1 (or 2)-indazolylmethyl)butyryl]phenoxy}acetic acid in the form of whiteneedles, M.P. 163-164".

Analysis for 'C H Cl N O .Calculated (percent): C, 57.02; H, 4.31; N,6.65. Found (percent): C, 57.34; H, 4.39; N, 6.97.

EXAMPLE 6 1 (or 3-[2-(2,3-dichloro-4-carboxymethoxybenzoyl) butyl]-1H(or 3H) -imidazo[4,5-b]pyridine To a solution of sodium bicarbonate(2.52 g., 0.03 mole) in water (100 ml.) is added [2,3-dichloro-4-(2-methylenebutyryl)phenoxy]acetic acid (9.09 g.; 0.03 mole). Then asolution of 4-azabenzimidazole (3.57 g.; 0.03 mole) in water (50 ml.) isadded and the resulting solution is allowed to stand at room temperaturein a nitrogen atmosphere. After 45 hours, the clear reaction solution istreated with one equivalent of 6 N hydrochloric acid to give a pH of3.0. The solid that separates is isolated by filtration, washed withwater and dried; the yield is 11.77 g. Recrystallization from adimethylformamide-ethanol mixture gives 7.31 g. (58%) of a 1 (or 3)- [2-(2,3 -dichloro-4-carboxymethoxybenzoyl) butyl] -1H (or 3H)-imidazo-[4,5-b] pyridine in the form of a white solid, M.P. 196-197.

Analysis for C H Cl N O .Calculated (percent): C, 54.04; H, 4.06; N,9.95. Found (percent): C, 53.71; H, 4.37; N, 9.77.

EXAMPLE 7 {2,3-dichloro-4- [2-( 1,2-triazol-1 (or 4)-ylmethyl)butyryl]phenoxy}acetic acid To a solution of sodium bicarbonate (2.52g., 0.03 mole) in water ml.) is added [2,3-dichloro-4-(2-methylenebutyryl)phenoxy]acetic acid (9.09 g., 0.03 mole). Then1,2,4-triazole (2.07 g., 0.03 mole) is added and the resulting solutionis stirred at room temperature in a nitrogen atmosphere. After 45 hours,the clear reaction solution is made acid to Congo red paper by theaddition of 6 N hydrochloric acid. The precipitate that separates isisolated by filtration and recrystallized from ethanol to give 7.82 g.(70%) of {2,3-dichloro- 4-[2-(1,2,4-triazol-1 (or4)-ylmethyl)butyryl]phenoxy} acetic acid in the form of white needles; asecond recrystallization from ethanol gives 6.97 g. of the product whichmelts at 17l.

Analysis for C H Cl N O .-Calculated (percent): C, 48.40; H, 4.06; N,11.29. Found (percent): C, 48.44; H, 3.97; N, 11.20.

EXAMPLE 8 2,3 -dichloro-4- 2- 3,5 -dimethyl- 1 -pyrazolylmethylbutyryl]phenoxy}acetic acid To a solution of sodium bicarbonate (2.52g., 0.03 mole) in water (100 ml.) is added [2,3-dichloro-4-(2-methylenebutyryl)phenoxy]acetic acid (9.09 g., 0.03

mole). Then a suspension of 3,5-dimethylpyrazole (2.88 g., 0.03 mole) inwater (75 ml.) is added. The resulting solution is adjusted to a pH of7.0 by the addition of aqueous sodium hydroxide solution and thenallowed to and concentrated aqueous hydrochloric acid (4 ml.) causingprecipitation of sodium chloride which is removed by filtration. Thefiltrate is dried over anhydrous sodium sulfate, filtered and heatedwith additional ether (500 ml.)

stand at room temperature. After 45 hours, the clear 5 whichprecipitates 5.0 g. (41%) of {2,3-dichloro-4-[2- reaction solution isacidified to a pH of 3.0 by theaddiethyl-3-(l-imidazolyl)propionyl]phenoxy}acetic acid hytion of 6 Nhydrochloric acid. The solid that separates drochloride which melts at169-173 C. after recrystalis removed by filtration, washed with waterand dried; lization from a mixture of isopropyl alcohol and ether. theyield is 10.87 g. After grinding under ether, filtering Analysis for C HCl O .Calculated (percent): and washing with ether, there is obtained9.77 g. (82%) C, 47.14; H, 4.20; N, 6.87. Found (percent): C, 46.97; of{2,3 dichloro 4 [2 (3,5 dimethyl 1 pyrazolyl- H, 4.08; N, 6.86. methyl)butyryl]phenoxy}acetic acid in the form of White In a manner similar tothat described in Example 1 prisms, M.P.154-l55. for the preparation of{2,3-dichloro-4-[1-oxo-2-ethyl-3- Analysis for C H Cl N O .Calculated(percent): (1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopurin-7 (or 9) C,54.15; H, 5.05; N, 7.02. Found (percent): C, 54.04;-yl)propyl]phenoxy}acetic acid all of the {4-[3-(polyaza- H, 5.19; N,17.08. heterocyclic)alkanoyl]phenoxy}alkanoic acid products of EXAMPLE 9the invention may be obtained. Thus, by substituting the appropriatepolyazaheterocycle and [4-(2-alkylideneacyl)iz3'dlchlom'4'[2'ethy13'(l'lmlfiazolynbutyryl] phenoxy]alkanoic acid forthe theophylline and [2,3-diphenoxy}acetlc acldchloro-4-(2-methylenebutyryl)phenoxy]acetic acid reac- To a olution ofodiu bi arbonate (252 g,, 0,03 tants recited in Example 1 and followingthe procedure mole) in water (100 ml.) is added [2,3-dichloro-4-(2-described therein all of the products of the invention mayethylidenebutyryl)phenoxy]acetic acid (9.52 g. 0.03 be obtained. Thefollowing equation illustrates the reacmole). Then a solution ofimidazole (2.04 g., 0.03 mole) t1011 of Example 1 wgefllef with Tableillustrates in water (50 ml.) is added and the resulting solution i thestarting materials of the instant process and the correallowed to standat room temperature. After 8 days, the spending products (Ib) derivedtherefrom: clear reaction solution is acidified to a pH of 3.0 by theaddition of 6 N hydrochloric acid. The precipitate that separates isisolated and recrystallized from isopropyl alcohol-ethyl acetatemixture. Further purification by recrystallization from ethanol gives1.44 g. (13%) of {2,3- X X dichloro 4 [2 ethyl 3 (1 imidazolyl)butyryl]I I Base H+ phenoxy}acetic acid in the form of white prisms, M.P.RC(i.-O-C..H2,,COOH 156 157 l Polyazaheterocyele l l i.e., R2H Analysisfor C H Cl N O .Calculated (percent): X X c, 53.00; H, 4.71; N, 7.27.Found (percent): c, 52.84; R2 H, 4.91; N, 7.17.

EXAMPLE 10 {2,3-dichloro-4- [2-ethyl-3-( l-imidazolyl propionyl] 3phenoxy}acetic acid hydrochloride 0 f A solution of2,3-dichloro-4-(Z-methylenebutyryl)- P; O CnH2nCOOH phenoxy]acetic acid(9.1 g., 0.03 mole) and sodium bi- I carbonate (2.52 g., 0.03 mole) inwater (150 ml.) is 5 e treated with imidazole (2.04 g., 0.03 mole) andstirred R2 at room temperature for 16 hours. The water is distilled fromthe reaction at reduced pressure at C. and the ID residue is dissolvedin ethanol (50 ml.), ether ml.)

TABLE I Example R R1 R2 X2 X3 X5 X OnH2u" H h 1-1- 1 H OH H H -CH-8EITGF3 H iti ji ndzoiii igi z i -yl. H0 a Cl 3 H H same as above. Sameas above. H 5-methyl-1 (or 3) CH=CH-CH=CH H H Do.

benzirnidazolyl. 14 do H 1 glsDbgor 3(i3ffl-imidazo CHa CHs H H Do. 15-CH(CH3)(CFi) H 1,2,a',s-teil ;h drb-1,3- H OH3 H H Do.

dimethyl-2,6-diox0purin-7 (or 9) -y1. 1e -C2H5 H 5-rnethyl-1(1H) [or3(3H)] H Cl H H Do.

imidazo(4,5-b]pyridy1. 17 Same as above.. H 1,2,3,6-tetrahydro-1,3- CHzCHa OHa H D0- diethy1-2,6-di0xopurin- 7 (or 9) -yl. 1s do Hfi-ethyl-IUH) [or 3(3H)] H 01 H H Do.

imidazo[4,5-b]pyridyl. 19 OH(OH3)2 H a (or 5) -methyl-1, 2,4- 01 or H HD0,

triazol-l (or 4) -yl. 20.; 02 5 H 4-rnethyl-1-imidazolyl H c1 01 HCH[CH-(CH 21 Same as above-. H fi-rlntithyl-l (or 2) -lndazo- CHa -CH3-CH3 OII3 -CH2 tigeih i-nza-trmzol-i Br 01 11 H Same as above. 1 $2:tetra-zolyl H 01 H H Do. 1,2,3,6-tetrahydro-1- H 01 H H D0.

The products of the invention can be administered in a wide variety oftherapeutic dosages in conventional vehicles as, for example, by oraladministration in the form of a capsule or tablet as well as byintravenous injection. Also, the dosage of the products may be variedover a wide range as, for example, in the form of capsules or scoredtablet containing 5, 10, 20, 25, 50, 100, 150, 250 and 500 milligrams,i.e., from to about 500 milligrams, of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thesedosages are well below the toxic or lethal dose of the products.

A suitable unit dosage form of the products can be prepared by mixing100 mg. of a {4[3-(polyazaheterocyclic)alkanolyl]phenoxy}alkanoic acidwith 94 mg. of lactose and 6 mg. of magnesium stearate, and placing the200 mg. mixture into a No. 3 gelatin capsule. Similarly, by employingmore of the active ingredient and less lactose, other dosage forms canbe put up in No. 3 gelatin capsules and, should it be necessary to mixmore than 200 mg. of ingredients together, larger capsules may beemployed. Compressed tablets, pills or other desired unit dosages can beprepared to incorporate the instant compounds by conventional methodsand, if desired, can be made up as elixirs or as injectable solutions bymethods well known to pharmacists.

It is also within the scope of this invention to combine two or more ofthe compounds of this invention in a unit dosage form or to combine oneor more of the compounds with other known diuretics and saluretics or xwith other desired therapeutic and/or nutritive agents in dosage unitform.

The following example is illustrative of the preparation of therepresentative dosage form:

EXAMPLE 25 Dry-filled capsules containing 100 mg. of active ingredientper capsule Mg. per capsule {2,3 dichloro 4[l-oxo-2-ethyl-3-(1,2,3,6-tetra hydro-1,3-dimethyl 2,6 dioxopurin-7 (or9) -yl)propyl]phenoxy}acetic acid 100 Lactose 94 Magnesium stearate 6Capsule size No. 3 200 The {2,3 dichloro 4[l oxo 2 ethyl-3-(1,2,3,6-tetrahydro-l,3-dimethyl 2,6 dioxopurin 7 or 9) -yl)-propyl]phenoxy}acetic acid is reduced to a No. 60 powder and thenlactose and magnesium stearate are passed through a No. 60 bolting clothonto the powder and the combined ingredients admixed for 10 minutes andthen filled into No. 3 dry gelatin capsules.

Similar dry-filled capsules can be prepared by replacing the activeingredient of the above example by any of the other novel compounds ofthis invention.

It will be understood that this invention also includes the salts,esters and amides of the instant acids which are compatible with thebody system and whose pharmacological properties will not cause adversephysiological effects. The salts may be formed as indicated in theforegoing examples except that the final acidification step is omitted.They may also be made by the direct addition of a suitable base to the{4-[3-(polyazaheterocyclic)alkanoyl1- phenoxy}acetic acid. Suitablebases which can be used to form the salts are, for example, the alkalimetal and alkaline earth metal hydroxides, carbonates, bicarbonates,etc., ammonia, primary, secondary and tertiary amines such asmonoalkylamines, dialkylamines, trialkylamines, nitrogen containingheterocyclic amines, for example, piperidine, etc.

Suitable esters and amides include, for example, the alkyl esters, thedialkylaminoalkyl esters and the amide,

'monoalkylamides, dialkylamides and heterocyclic amide derivatives as,for example, amides derived from heterocyclic amines as pyrrolidine,piperidine, morpholine, etc. The esters and amides are prepared by thesame procedures set forth in the examples hereinbefore except that the[4-(2-alkylidenacyl)phenoxy]alkanoic acid is first converted to thedesired ester or amide as the starting material. In this case theaddition of the base is used solely to raise the pH since there is nosalt formation. Also it is often necessary to add a solvent such as alower alkanol, dimethylformamide and the like. They also may be preparedfrom the acid halide derivatives of the {4-[3-(polyazaheterocyclic)alkanoyl]phenoxy}alkanoic acids by reaction with asuitable alcohol, ammonia, monoalkylamine, dialkylamine orheterocyclicamine.

The foregoing and other equivalent methods for the preparation of thesalts, esters and amide derivatives of the instant products will beapparent to those having ordinary skill in the art and, to the extentthat the said derivatives are both nontoxic and physiologicallyacceptable to the body system, the said esters and amides are thefunctional derivatives of the corresponding acids.

It will be apparent from the foregoing description that the {4 [3(polyazaheterocyclic) alkanoyl]phenoxy}alkanoic acids and their salts,esters and amides constitute a valuable class of compounds which havenot hitherto been prepared. One skilled in the art will also appreciatethat the processes disclosed in the above examples are merelyillustrative and are capable of variation and modification withoutdeparting from the spirit of the invention.

What is claimed is:

1. A compound of the general formula:

wherein R is selected from the group consisting of straight and branchedchain lower alkyl, and trifiuoromethyl substituted lower alkyl; R isselected from the group consisting of hydrogen and straight and branchedchain lower alkyl; R is 1,2,3,6-tetrahydro-1,3-di-lower alkyl2,6-dioxopurin-7 (or 9) -yl; X is selected from the group consisting ofhydrogen, halogen, and straight and branched chain lower alkyl, and whentaken together two X radicals on adjacent carbon atoms of the benzenering may be joined to form the 1,3-butadienylene linkage; m is aninteger from 1-4 and n is an integer from l-4 and the pharmaceuticallyacceptable salts thereof.

2. A compound of the general formula:

wherein R is selected from the group consisting of straight and branchedchain lower alkyl; R is l,2,3,6-tetrahydro- 1,3-di-loweralkyl-2,6-dioxopurin-7 (or 9) -yl; and X and X are selected from thegroup consisting of hydrogen, halogen and straight and branched chainlower alkyl, and

9 10 when taken together with the carbon atoms of the benzene OTHERREFERENCES lfiing a g} g. q i they may be lomed to Wagner and Zook,Synthetic, Organic Chemistry, New

orm e u a ieny ene m age.

3. The compound of claim 2 wherein R is hydrogen, York, John Wiley &Sons, 1953, (pp. 672 673 relied on).

X and X are chlorine, and R is 1,2,3,6-tetrahydro-1,3- 5 ALEX M AZELPrimary Examiner dimethyl-2,6-di0xopurin-7 (or 9) -y1.

A. M. T. TI'GHE, Assistant Exammer References Cited US. Cl. X.R.

UNITED STATES PATENTS 3,422.107 1/1969 Mohler et a1 260255 1O 310C,310R, 311, 520, 521R, 521A; 424253 260247.7K, 253, 2947G, 295R, 308A, D,R, 309, 309.2,-

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,585,199 Dated June 15, 1971 Inventor) Ed ard ,1, Craggg. Jr.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

In column 2, line 6, "pyridil" should be pyridyl In column 3, line 17,"solutio" should be solution In column 4, line 8, "0.3" should be 0.03

In column 4, title of Example No. 7, "l,2triazol-" should be l,2,4-triazol- In column 5, line 16, "N, 17.08" should be N, 7.08

In Table I, Example No. 17 between column headings X and X delete Signedand sealed this 16th day of November 1971 (SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer ActingCommissioner of Patents

